Endothelin-1

ET-1 binds ETA receptors on vascular smooth muscle cells, activating Gq (PLC/IP3/calcium release) and G12/13 (Rho kinase/RhoA) pathways that produce sustained vasoconstriction and promote smooth muscle proliferation and hypertrophy. ETB receptors on endothelial cells activate eNOS to produce NO and prostacyclin, producing transient vasodilation before the dominant ETA-mediated constriction prevails at higher ET-1 concentrations.

Beyond acute vasoconstriction, ET-1 activates growth factor-like signaling through ETA receptors, promoting vascular smooth muscle cell proliferation, migration, and collagen synthesis. These effects drive pathological vascular remodeling in pulmonary arterial hypertension, where medial hypertrophy and adventitial fibrosis obliterate pulmonary arterioles. Chronic ET-1 exposure also activates cardiac fibroblasts, contributing to cardiac hypertrophy and fibrosis.

ET-1 levels are markedly elevated in PAH and correlate with disease severity and prognosis. Endothelin receptor antagonists (ERAs) including bosentan, ambrisentan, and macitentan are first-line therapies for PAH, reducing pulmonary vascular resistance, improving exercise capacity, and delaying clinical worsening. These drugs validate ET-1 as a critical PAH driver.

Plasma ET-1 correlates with heart failure severity, pulmonary hypertension, and left ventricular dysfunction. Research infusion of ET-1 in healthy subjects produces dose-dependent increases in blood pressure and vascular resistance, confirming its vasoconstrictor potency. ET-1 infusion models are used in human physiology studies to evaluate vascular reactivity.

ET-1 mediates renal vasoconstriction and sodium retention, contributing to hypertension in diabetic nephropathy and chronic kidney disease. ETB receptor-mediated ET-1 clearance by the kidney is impaired in CKD, elevating circulating ET-1. ETB agonism in the kidney has been explored as a natriuretic strategy.